Gene expression profiles for predicting the efficacy of the anticancer drug 5-fluorouracil in breast cancer.
ABSTRACT Chemotherapy is an important postsurgery adjuvant therapy in the treatment of breast cancer. However, because of the individual genotype differences of patients, the drug efficacy differs from person to person, even when the same chemotherapy drug is administered. The purpose of this research was to probe the gene expression profiles to predict the efficacy of 5-fluorouracil (5-FU), the common drug used in chemotherapy for various type of cancers, in Taiwanese breast cancer patients. Microarray analysis was conducted on the cancer cell line ZR-75-1 with and without 5-FU stimulation to identify the differentially expressed genes. The significant overexpressed gene groups were selected after bioinformatics software analysis to explore the molecular mechanism of 5-FU. Six strains of breast cancer cell line purchased from American Type Culture Collection were used to analyze the expression profiles of the above target gene groups. IL18, CCL28, CXCL2, SOD1, HRAS, FDXR, and CHI3L1 genes were significantly differentially expressed in 5-FU responder and nonresponder cell lines. The selected gene groups were validated with 20 strains of breast cancer primary cultures established previously in our laboratory. The experimental results demonstrated that FAM46A, IL18, CCL28, TNF, CXCL2, PLEKHA8, HRAS, FDXR, and CHI3L1 genes showed statistically significant differential expression between primary breast cancer culture cells that respond and nonrespond to 5-FU. Six genes, IL18, CCL28, CXCL2, HRAS, FDXR, and CHI3L1, showed significant differential expression pattern in both American Type Culture Collection and primary breast cancer cultured cells. The findings of this study may serve as basis for predicting the effectiveness of 5-FU on breast cancer.
- The Lancet 08/1974; 2(7873):171-2. · 39.06 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We demonstrate a highly significant relationship (p less than 0.0001) between the incorporation of 5-flourouracil in total cellular RNA and loss of clonogenic survival of the human MCF-7 breast carcinoma cell line. The extent of 5-fluorouracil incorporation in RNA is concentration- and time-dependent. Identical results are obtained in experiments employing thymidine to bypass the block of thymidylate synthetase and reverse inhibition of DNA synthesis. These studies suggest that the incorporation of 5-fluorouracil in RNA is the major mechanism of cytotoxic action in this human cell line.Journal of Biological Chemistry 11/1981; 256(19):9802-5. · 4.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The cytokinetic and biochemical effects of 5-fluorouracil and 5-fluorouridine were examined in a human colon carcinoma cell line (HT-29) in culture. Logarithmically growing cells were approximately 100 times more sensitive to the lethal effects of 5-fluorouridine than 5-fluorouracil as measured by colony formation in soft agar medium. A 2-hr exposure of cells to 10(-3) M 5-fluorouracil or 10(-5) M 5-fluorouridine produced a 2-log reduction in colony formation, a 31--33% inhibition of [14C]deoxyguanosine incorporation into DNA, and 30--40% inhibition of [3H]adenosine incorporation into total RNA. Increasing the duration of drug exposure to 24 hr produced a proportional reduction in the drug concentration required to produce similar biochemical and cytocidal effects. However, cell lethality produced by either drug did not correlate quantitatively with inhibition of DNA or RNA synthesis. Examination of nuclear rRNA and 4 S RNA synthesis by agarose gel electrophoresis following 2-hr and 24-hr exposure to 5-fluorouracil or 5-fluorouridine indicated that processing of rRNA was not impaired, rRNA synthesis was inhibited by 10--40%, and 4 S RNA synthesis was unaffected. In contrast to these results, measurements of the incorporation fo [3H]5-fluorouracil or [3H]5-fluorouridine into nuclear RNA showed that a significant correspondence existed between the amount of drug incorporated into nuclear RNA and cell lethality. These results indicate that the primary determinant of cell lethality in HT-29 cells is the degree of fluoropyrimidine substitution in nuclear RNA and not inhibition of either DNA or RNA synthesis.Molecular Pharmacology 04/1982; 21(2):468-73. · 4.41 Impact Factor